Spontaneous intracerebral hemorrhage (ICH) is associated with high morbidity and mortality. Despite its clinical importance, however, there is little known about the pathogenesis of ICH and the edema that forms around it. Consequently there is no specific therapy. We intend to study the mechanisms of brain edema formation which follows acute ICH in order to develop rational treatment strategies for patients with that condition. Our proposal is based upon a highly reproducible model of ICH in the rat which we have developed. The project includes experiments designed to determine why a blood clot in brain parenchyma causes surrounding edema, increasing mass effect, and progressive neurological deterioration. We will consider two alternate, but not mutually exclusive, hypotheses. One tests the idea that brain edema following ICH results from mass effect which causes regional ischemia, disruption of the blood-brain barrier and ischemic edema. As a consequence edema control would be based primarily on elimination of mass effect caused by the clot. The experiments designed to address this hypothesis involve measurements of cerebral blood flow, brain edema, and blood-brain barrier permeability at various times after the introduction of a blood clot or an inert mass of equal volume into the caudate nucleus. The second hypothesis is based upon the idea that ICH causes an interaction between components of the clot and brain parenchyma resulting in blood-brain barrier disruption and edema formation. In this case, edema control would be more properly based on manipulation of edemagenic factors by local or systemic pharmacologic agents. Experiments will compare the effect on brain edema and blood-brain barrier permeability of the injection of specific biochemical substances that could be released from the clot and the therapeutic efficacy of treating animals with pharmacologic agents that inhibit the actions of those substances.